Communication pubs.acs.org/JACS
Remote Ester Groups Switch Selectivity: Diastereodivergent Synthesis of Tetracyclic Spiroindolines Jun Zhu,† Yong Liang,‡ Lijia Wang,† Zhong-Bo Zheng,† K. N. Houk,*,‡ and Yong Tang*,† †
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Lu, Shanghai 200032, China ‡ Department of Chemistry and Biochemistry, University of California, Los Angeles, California 90095, United States S Supporting Information *
of this stereochemical control are also determined by density functional theory (DFT) calculations. Initial attempts began with the intramolecular [3 + 2] annulation of newly designed cyclopropane 1. In the presence of 10 mol % of Sc(OTf)3, the reaction proceeded very well at 70 °C in 1,2-dichloroethane (DCE), giving the tetracyclic spiroindoline in 80% yield as shown in Table 1 (entry1).
ABSTRACT: Stereocontrol in the synthesis of structurally complex molecules, especially those with all-carbon quaternary stereocenters, remains a challenge. Here, we reported the preparation of a class of tetracyclic cyclopenta-fused spiroindoline skeletons through Cu(II)catalyzed intramolecular [3 + 2] annulation reactions of donor−acceptor cyclopropanes with indoles. Both cis- and trans-diastereomers of tetracyclic spiroindolines are accessed with high selectivities by altering the remote ester groups of cyclopropanes. The origins of this stereocontrol are identified using DFT calculations: attractive interactions between the ester group and arene favor the generation of the trans isomer, while the formation of the cis isomer is preferred when steric repulsions become predominant.
Table 1. Reaction Optimization
P
olycyclic spiroindolines are constituents of many alkaloid natural products1 as well as some biologically active molecules.2 Considerable efforts have been devoted to the synthesis of this motif.3 Of those synthetic methods developed, indole based cycloaddition3b,g and cascade reactions3e,f,h,i have shown extraordinary elegance and efficiency. As chemical transformations of donor−acceptor (D−A) cyclopropanes were elucidated to be useful in organic synthesis,4−7 we conceived that an intramolecular reaction might offer a new strategy to prepare a class of tetracyclic cyclopenta-fused spiroindoline skeletons by joining the indole and cyclopropane with a linker (Scheme 1). Here, we describe the development of
Lewis acid
L
solvent
yield (%)b
dr (2/3)c,d
1 2 3 4 5 6 7e 8e 9e 10e 11e
Sc(OTf)3 Cu(SbF6)2 Cu(SbF6)2 Cu(SbF6)2 Cu(SbF6)2 Cu(SbF6)2 Cu(SbF6)2 Cu(SbF6)2 Cu(SbF6)2 Cu(SbF6)2 Cu(SbF6)2
− L1 L2 L3 L4 L5 L3 L3 L3 L3 L3
DCE DCE DCE DCE DCE DCE DCE toluene THF CH3CN DMSO
80 57 55 61 87 26 83 73 trace NR NR
50/50 66/34 75/25 83/17 55/45 54/46 83/17 81/19 76/24 − −
a
Conducted on 0.25 mmol scale, solvent (4 mL), reaction time: 4−48 h. bIsolated yields of products 2 and 3. cDetermined by 1H NMR spectroscopy of the crude products. dThe cis isomer is defined by Hatoms on the tertiary carbon which are on the same side of the cyclopentyl ring. The trans is defined by H-atoms on the tertiary carbon which are on opposite sides of the cyclopentyl ring. eAt 30 °C.
Scheme 1. Newly-Designed Intramolecular [3+2] Annulation Approach to Tetracyclic Spiroindolines
Unfortunately, the diastereoselectivity is very poor. Then we explored the common strategies8 such as by optimizing the Lewis acids,8a reaction conditions,8b−f and ligands8g to improve the stereoselectivity. When In(OTf)3 and Cu(ClO4)2·6H2O were employed, poor diastereoselectivities were obtained (see Supporting Information (SI), Table S1, entries 2 and 11). By using Zn(OTf)2, the annulation was sluggish (Table S1, entry 8).
this approach to tetracyclic spiroindolines with three continuous stereocenters including an all-carbon quaternary stereocenters in a five-membered ring. In particular, we observed that the diastereoselectivity of this new reaction can be switched by changing the remote ester groups of cyclopropanes: the isopropyl ester is highly favorable for the trans diastereomer, while the 2-adamantyl ester is the best for the cis one. The origins © 2014 American Chemical Society
entrya
Received: March 27, 2014 Published: April 25, 2014 6900
dx.doi.org/10.1021/ja503117q | J. Am. Chem. Soc. 2014, 136, 6900−6903
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To investigate the generality of this reaction, we synthesized a variety of cyclopropanes 1 with 2-propyl and 2-adamantyl ester groups. Under the optimal conditions, we first evaluated with isopropyl esters (iPr-1) for the synthesis of trans product 2. As shown in Table 3, substituents such as F, Cl, Br, and alkyl on the
When the reaction was catalyzed by Cu(SbF6)2 (10 mol %) in the presence of diimine ligand L1, we were pleased to find that the reaction speeded up significantly and finished in 4 h with 66/34 dr in 57% yield (entry 2). More hindered diimine ligands provide better stereoselectivities (entries 2−4). To our delight, when N2,6-diisopropylphenyl diimine L3 was employed as the ligand, the yield and diastereoselectivity increased to 61% and 83/17, respectively (entry 4). Other ligands such as bisoxazoline L4 and bipyridine L5 were also examined, but resulted in poor diastereoselectivities (55/45 and 54/46 dr, entries 5 and 6). Lowering the reaction temperature to 30 °C afforded an 83% yield without erosion of diastereoselectivity (entry 7). Solvent screening showed that toluene could lead to a 73% yield and 81/ 19 dr, but THF, acetonitrile, and DMSO proved to be unsuitable in this reaction (entries 8−11). After hundreds of trials failed to improve the diastereoselectivity to a satisfactory result (for details, see SI), we focused on changing the ester R group of the cyclopropane. As shown in Table 2, when the R group of the ester was changed from ethyl to
Table 3. Reaction Scope with Isopropyl Esters
Table 2. Effect of Ester Groups
entrya
R′
R
yield (%)b
dr (2/3)c
1 2 3 4 5 6 7 8 9 10 11 12 13
H H H H H H H H H H H CH3 CH3
Et Me nHex iPr cHex 3-Pent tBu 1-Ad CH2tBu CH2-1-Ad 2-Ad iPr 2-Ad
83 87 77 77 83 45 trace trace 64 52 61 85 79
83/17 74/26 78/22 90/10 88/12 89/11 − − 15/85 9/91 6/94 84/16 5/95
entrya
R
product
yield (%)b
dr (trans/cis)c
1 2 3 4 5 6 7 8 9 10 11 12 13
H 5-Me 5-F 5-Cl 5-Br 6-F 6-Cl 7-Me 7-Br 4-Me 4-F 4-Cl 4-Br
2ad 2b 2c 2d 2e 2f 2g 2h 2i 2j 2k 2l 2m
77 71 77 84 83 60 73 80 84 50 71 68 81
90/10 94/6 93/7 93/7 93/7 88/12 89/11 91/9 94/6 >99/1 95/5 >99/1 >99/1
a
Conducted on 0.25 mmol scale, DCE (4 mL). bIsolated yields. Determined by 1H NMR spectroscopy of the crude products. d Confirmed by X-ray diffraction analysis. c
indole, as well as different substitution patterns (4, 5, 6, 7-), are well tolerated in the reaction, giving the desired products in good yields with high diastereoselectivities (from 88/12 to >99/1 dr, entries 2−11). With electron-donating and -withdrawing groups at different positions of the aromatic ring of indole, in cases of 2adamantyl ester substrates (Ad-1), the reactions showed good reactivity and excellent diastereoselectivities affording cis tetracyclic spiroindolines 3 (72−95% yield, 93/7−96/4 dr; Table 4, entries 2−10). In addition, the reactions in Tables 3 and Table 4. Reaction Scope with 2-Adamantyl Esters
a
Conducted on 0.25 mmol scale, DCE (4 mL). bIsolated yields of products 2 and 3. cDetermined by 1H NMR spectroscopy of the crude products. Pent = pentyl; Ad = adamantyl.
methyl, the diastereomeric ratio was decreased to 74/26 (entry 2), suggesting that the ester groups on the cyclopropane ring may have a significant influence on the selectivity. Therefore, a variety of substrates 1 with different ester groups were examined in this intramolecular [3 + 2] annulation. It was found that changing the ester R group from a primary to secondary alkyl group can improve the diastereoselectivity greatly (entries 2−6).9 The isopropyl group proved to be optimal with respect to the selective synthesis of trans diastereomer 2 (2/3: 90/10, entry 4). Continuing to increase the size of esters by introducing tertiary alkyl groups, such as tert-butyl and 1-adamantyl, destroyed the reactivity (entries 7−8). To our surprise, a sudden inversion of selectivity to cis diastereomer 3 (2/3: 15/85, entry 9) was observed when neo-pentyl ester was used, and the cis/trans ratio can be further elevated to 94/6 by employing the 2-adamantyl group (entry 11). This diastereo-divergence switched by the ester group was also observed in the reactions using the corresponding N-methylindole substrates (entries 12−13).
entrya
R
product
yield (%)b
dr (cis/trans)c
1 2e 3 4 5 6 7 8 9 10e
H 5-OMe 5-Me 5-F 5-Cl 5-Br 6-F 6-Cl 7-Me 4-OMe
3ad 3b 3c 3d 3e 3f 3g 3h 3i 3j
79 95 90 92 93 84 93 91 92 72
95/5 95/5 96/4 95/5 94/6 95/5 93/7 94/6 96/4 95/5
a
Conducted on 0.25 mmol scale, DCE (4 mL). bIsolated yields. Determined by 1H NMR spectroscopy of the crude products. d Confirmed by X-ray diffraction analysis. eWith 20 mol % catalyst. Ad = 2-adamantyl. c
6901
dx.doi.org/10.1021/ja503117q | J. Am. Chem. Soc. 2014, 136, 6900−6903
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4 were carried out under very mild conditions and finished within 24 h. The stereochemistries of 2a and 3a were identified by X-ray analysis.10 The current method is suitable to prepare chiral tetracyclic spiroindolines. As shown in Scheme 2, when the optically pure Scheme 2. Synthesis of Chiral Tetracyclic Spiroindolines from Optically Pure Substrates
isopropyl or 2-adamantyl substrate was employed, the chirality from the cyclopropane is completely transferred to the product, similar to the cycloaddition11 of aldehydes and D−A cyclopropanes. The aforementioned results showed excellent generality of the current reaction and that 2-propyl esters iPr-1 gave trans-isomers 2 while 2-adamantyl esters Ad-1 afforded cis-isomers 3. As the 2propyl and 2-adamantyl groups are remote to the first reactive site and both are secondary alkyl groups, it is hard to explain the effect of the ester group on the stereochemistry by only its steric hindrance and electronic properties. To further understand the mechanism of the intramolecular annulation of indole with a D− A cyclopropane, especially the origins of the unique diastereoselectivity control by the remote ester groups, DFT calculations were performed on four reactions with different R groups shown in Scheme 3.12 Once cyclopropane-1,1-dicarbox-
Figure 1. DFT-optimized structures of transition states TS1-trans-R and TS1-cis-R and DFT-computed relative activation Gibbs free energies (R = Me, iPr, CH2tBu, 2-Ad; carbon, gray; nitrogen, blue; oxygen, red; sulfur, yellow; copper, brown; H-atoms are not shown for clarity; distances are given in angstroms).
trans configuration via TS2-trans-R or the cis one via TS2-cis-R (Scheme 3). As shown in Figure 1, for the reaction with the methyl ester, DFT calculations using the ωB97XD13 and B3LYP14 methods indicate that formation of the trans product via TS1-trans-Me is slightly favored, in agreement with the experimental result (Table 2, entry 2). In the case of the isopropyl ester, a better trans selectivity is obtained experimentally (Table 2, entry 4). This trend is only reproduced by the ωB97XD method, which yields better results when describing medium- to long-range electron correlation and dispersion effects than those from the traditional B3LYP method.13,15 As the size of the R group from methyl to isopropyl increases, there is no significant steric repulsion generated between the ester and arene in the transition state TS1-trans-iPr, but the attractive interactions,16 which include dispersion forces,17become stronger. In the Wilcox molecular torsion balance experiment, it was reported that the noncovalent interactions between isopropyl and arene are ∼0.5 kcal mol−1 larger than the methyl-arene interactions in the organic solvent.18 This value is very close to the ωB97XD energy difference for the enhanced trans selectivity (Me: −0.4 kcal mol−1, iPr: −0.7 kcal mol−1, Figure 1). When the R group becomes much bulkier (R = CH2tBu, 2-Ad), the steric repulsions increase dramatically in the transition state TS1-trans-R as evidenced by the elongated forming C−C bond (2.76 vs 2.60−2.62 Å, to avoid steric clashes, Figure 1). Therefore, the formation of cis products via TS1-cisCH2tBu(2-Ad) is preferred.
Scheme 3. DFT Study on Intramolecular [3 + 2] Reactions Involving Different Ester Groups
ylate is activated by a Cu(II) catalyst, the intramolecular indole C3-nucleophilic attack to the cyclopropane C2 carbon generates two diastereomeric intermediates through transition states TS1trans-R and TS1-cis-R, respectively (Figure 1). Computational results show that regardless of the size of the R group, this step is irreversible (for details, see the SI), determining the stereochemistry of final products. The subsequent ring-closure process leads to the cycloadduct with two methine hydrogen atoms in a 6902
dx.doi.org/10.1021/ja503117q | J. Am. Chem. Soc. 2014, 136, 6900−6903
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(5) For selected leading references of intermolecular asymmetric anulation of D−A cyclopropane, see: (a) Sibi, M. P.; Ma, Z. H.; Jasperse, C. P. J. Am. Chem. Soc. 2005, 127, 5764. (b) Kang, Y. B.; Sun, X. L.; Tang, Y. Angew. Chem., Int. Ed. 2007, 46, 3918. (c) Parsons, A. T.; Johnson, J. S. J. Am. Chem. Soc. 2009, 131, 3122. (d) Parsons, A. T.; Smith, A. G.; Neel, A. J.; Johnson, J. S. J. Am. Chem. Soc. 2010, 132, 9688. (e) Trost, B. M.; Morris, P. J. Angew. Chem., Int. Ed. 2011, 50, 6167. (f) Xiong, H.; Xu, H.; Liao, S.; Xie, Z.; Tang, Y. J. Am. Chem. Soc. 2013, 135, 7851. (g) Xu, H.; Qu, J. P.; Liao, S.; Xiong, H.; Tang, Y. Angew. Chem., Int. Ed. 2013, 52, 4004. (h) Zhou, Y. Y.; Li, J.; Ling, L.; Liao, S. H.; Sun, X. L.; Li, Y. X.; Wang, L. J.; Tang, Y. Angew. Chem., Int. Ed. 2013, 52, 1452. (6) For selected leading references of intramolecular anulation of cyclopropane, see: (a) Danishefsky, S. Acc. Chem. Res. 1979, 12, 66. (b) Jackson, S. K.; Karadeolian, A.; Driega, A. B.; Kerr, M. A. J. Am. Chem. Soc. 2008, 130, 4196. (c) Xing, S.; Pan, W.; Liu, C.; Ren, J.; Wang, Z. Angew. Chem., Int. Ed. 2010, 49, 3215. (d) Xing, S.; Li, Y.; Li, Z.; Liu, C.; Ren, J.; Wang, Z. Angew. Chem., Int. Ed. 2011, 50, 12605. (e) Bai, Y.; Tao, W.; Ren, J.; Wang, Z. Angew. Chem., Int. Ed. 2012, 51, 4112. (f) Zhu, W.; Fang, J.; Liu, Y.; Ren, J.; Wang, Z. Angew. Chem., Int. Ed. 2013, 52, 2032. (g) Cavitt, M. A.; Phun, L. H.; France, S. Chem. Soc. Rev. 2014, 43, 804. (7) (a) Harrington, P.; Kerr, M. A. Tetrahedron Lett. 1997, 38, 5949. (b) Kerr, M. A.; Keddy, R. G. Tetrahedron Lett. 1999, 40, 5671. (c) England, D. B.; Kuss, T. D.; Keddy, R. G.; Kerr, M. A. J. Org. Chem. 2001, 66, 4704. (d) Bajtos, B.; Yu, M.; Zhao, H.; Pagenkopf, B. L. J. Am. Chem. Soc. 2007, 129, 9631. (e) Larquetoux, L.; Ouhamou, N.; Chiaroni, A.; Six, Y. Eur. J. Org. Chem. 2005, 2005, 4654. (8) For selected leading references, see: (a) Lu, G.; Yoshino, T.; Morimoto, H.; Matsunaga, S.; Shibasaki, M. Angew. Chem., Int. Ed. 2011, 50, 4382. (b) Moteki, S. A.; Han, J.; Arimitsu, S.; Akakura, M.; Nakayama, K.; Maruoka, K. Angew. Chem., Int. Ed. 2012, 51, 1187. (c) Krautwald, S.; Sarlah, D.; Schafroth, M. A.; Carreira, E. M. Science 2013, 340, 1065. (d) Oliveira, M. T.; Luparia, M.; Audisio, D.; Maulide, N. Angew. Chem., Int. Ed. 2013, 52, 13149. (e) Sun, X.-L.; Tang, Y. Acc. Chem. Res. 2008, 41, 937. (f) Deng, X.-M.; Cai, P.; Ye, S.; Sun, X.-L.; Liao, W.-W.; Li, K.; Tang, Y.; Wu, Y.-D.; Da, L.-X. J. Am. Chem. Soc. 2006, 128, 9730. (g) Ding, S.; Song, L.-J.; Chung, L. W.; Zhang, X.; Sun, J.; Wu, Y.-D. J. Am. Chem. Soc. 2013, 135, 13835. (9) When the benzyl ester was examined, a 75% yield with 55/45 (trans/cis) was obtained. (10) CCDC 981305 (2a) and 981312 (3a) contain the supplementary crystallographic data for this paper. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www. ccdc.cam.ac.uk/data_request/cif. (11) Pohlhaus, P. D.; Johnson, J. S. J. Am. Chem. Soc. 2005, 127, 16014. (12) (a) Frisch, M. J. et al. Gaussian 09, Revision C.01; Gaussian, Inc.: Wallingford, CT, 2010. Complete reference is in the SI. (b) Geometry optimizations and frequency calculations were performed at the B3LYP/6-31G(d)-LANL2DZ (for Cu) level. Single-point energy calculations in 1,2-dichloroethane (DCE) using the CPCM model were performed at the B3LYP/6-311G(d,p)-LANL2DZ or ωB97XD/6311G(d,p)-LANL2DZ level. For details, see the SI. (13) Chai, J. D.; Head-Gordon, M. Phys. Chem. Chem. Phys. 2008, 10, 6615. (14) (a) Lee, C.; Yang, W.; Parr, R. G. Phys. Rev. B 1988, 37, 785. (b) Becke, A. D. J. Chem. Phys. 1993, 98, 5648. (15) Fokin, A. A.; Chernish, L. V.; Gunchenko, P. A.; Tikhonchuk, E. Y.; Hausmann, H.; Serafin, M.; Dahl, J. E.; Carlson, R. M.; Schreiner, P. R. J. Am. Chem. Soc. 2012, 134, 13641. (16) Krenske, E. H.; Houk, K. N. Acc. Chem. Res. 2013, 46, 979. (17) Schreiner, P. R.; Chernish, L. V.; Gunchenko, P. A.; Tikhonchuk, E. Y.; Hausmann, H.; Serafin, M.; Schlecht, S.; Dahl, J. E.; Carlson, R. M.; Fokin, A. A. Nature 2011, 477, 308. (18) Bhayana, B.; Wilcox, C. S. Angew. Chem., Int. Ed. 2007, 46, 6833.
In summary, we have succeeded in developing a simple, efficient method for the highly diastereoselective construction of tetracyclic spiroindoline skeletons through Cu(II)-catalyzed intramolecular [3 + 2] reactions of cyclopropane-1,1-dicarboxylates with indoles. Unprecedentedly, the diastereoselectivities of the present reaction could be readily switched by altering the remote ester groups of cyclopropanes: the isopropyl ester is highly favorable for the trans diastereomer, while the 2adamantyl ester is the best for the cis one. Thus, it provides not only a new approach for the remote control of diastereoselection but also a one-step and facile access to both cis- and trans-diastereomers of tetracyclic spiroindolines under the same reaction conditions. DFT calculations show that attractive interactions between the isopropyl ester and arene enhance the trans selectivity, and that the steric repulsions caused by the bulky 2-adamantyl group make the cis product predominant.
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ASSOCIATED CONTENT
S Supporting Information *
Experimental procedures, characterizations and analytical data of products, spectra of NMR and HPLC, and computational details. This material is available free of charge via the Internet at http:// pubs.acs.org.
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AUTHOR INFORMATION
Corresponding Authors
[email protected] [email protected] Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS We are grateful for the financial support from the National Natural Sciences Foundation of China (Nos. 21121062, 20932008, and 21272250), the Chinese Academy of Sciences, and the U.S. National Science Foundation (CHE-1059084). We thank Dr. Xue-bing Leng (SIOC) and Mr. Jie Sun (SIOC) for Xray crystal analysis.
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REFERENCES
(1) (a) Robinson, R. Experientia 1946, 2, 28. (b) Millson, M. F.; Robinson, R.; Thomas, A. F. Experientia 1953, 9, 89. (c) Verbitski, S. M.; Mayne, C. L.; Davis, R. A.; Concepcion, G. P.; Ireland, C. M. J. Org. Chem. 2002, 67, 7124. (d) Jadulco, R.; Edrada, R. A.; Ebel, R.; Berg, A.; Schaumann, K.; Wray, V.; Steube, K.; Proksch, P. J. Nat. Prod. 2004, 67, 78. (2) (a) Patchett, A. A.; Nargund, R. P.; Tata, J. R.; Chen, M. H.; Barakat, K. J.; Johnston, D. B.; Cheng, K.; Chan, W. W.; Butler, B.; Hickey, G.; et al. Proc. Natl. Acad. Sci. U.S.A. 1995, 92, 7001. (b) Elliott, J. M.; Broughton, H.; Cascieri, M. A.; Chicchi, G.; Huscroft, I. T.; Kurtz, M.; MacLeod, A. M.; Sadowski, S.; Stevenson, G. I. Bioorg. Med. Chem. Lett. 1998, 8, 1851. (3) (a) Bonjoch, J.; Sole, D. Chem. Rev. 2000, 100, 3455. (b) Boonsombat, J.; Zhang, H.; Chughtai, M. J.; Hartung, J.; Padwa, A. J. Org. Chem. 2008, 73, 3539. (c) Trost, B.; Brennan, M. Synthesis 2009, 2009, 3003. (d) Sirasani, G.; Paul, T.; Dougherty, W., Jr.; Kassel, S.; Andrade, R. B. J. Org. Chem. 2010, 75, 3529. (e) Cai, Q.; Zheng, C.; Zhang, J. W.; You, S. L. Angew. Chem., Int. Ed. 2011, 50, 8665. (f) Jones, S. B.; Simmons, B.; Mastracchio, A.; MacMillan, D. W. Nature 2011, 475, 183. (g) Martin, D. B. C.; Vanderwal, C. D. Chem. Sci. 2011, 2, 649. (h) Fan, F.; Xie, W.; Ma, D. Chem. Commun. 2012, 48, 7571. (i) Fan, F.; Xie, W. Q.; Ma, D. W. Org. Lett. 2012, 14, 1405. (4) Carson, C. A.; Kerr, M. A. Chem. Soc. Rev. 2009, 38, 3051. 6903
dx.doi.org/10.1021/ja503117q | J. Am. Chem. Soc. 2014, 136, 6900−6903
Remote Ester Groups Switch Selectivity: Diastereodivergent Synthesis of Tetracyclic Spiroindolines Jun Zhu,† Yong Liang,‡ Lijia Wang,† Zhong-Bo Zheng,† K. N. Houk,*,‡ and Yong Tang*,† †
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Lu, Shanghai 200032, China ‡ Department of Chemistry and Biochemistry, University of California, Los Angeles, California 90095, United States S Supporting Information *
of this stereochemical control are also determined by density functional theory (DFT) calculations. Initial attempts began with the intramolecular [3 + 2] annulation of newly designed cyclopropane 1. In the presence of 10 mol % of Sc(OTf)3, the reaction proceeded very well at 70 °C in 1,2-dichloroethane (DCE), giving the tetracyclic spiroindoline in 80% yield as shown in Table 1 (entry1).
ABSTRACT: Stereocontrol in the synthesis of structurally complex molecules, especially those with all-carbon quaternary stereocenters, remains a challenge. Here, we reported the preparation of a class of tetracyclic cyclopenta-fused spiroindoline skeletons through Cu(II)catalyzed intramolecular [3 + 2] annulation reactions of donor−acceptor cyclopropanes with indoles. Both cis- and trans-diastereomers of tetracyclic spiroindolines are accessed with high selectivities by altering the remote ester groups of cyclopropanes. The origins of this stereocontrol are identified using DFT calculations: attractive interactions between the ester group and arene favor the generation of the trans isomer, while the formation of the cis isomer is preferred when steric repulsions become predominant.
Table 1. Reaction Optimization
P
olycyclic spiroindolines are constituents of many alkaloid natural products1 as well as some biologically active molecules.2 Considerable efforts have been devoted to the synthesis of this motif.3 Of those synthetic methods developed, indole based cycloaddition3b,g and cascade reactions3e,f,h,i have shown extraordinary elegance and efficiency. As chemical transformations of donor−acceptor (D−A) cyclopropanes were elucidated to be useful in organic synthesis,4−7 we conceived that an intramolecular reaction might offer a new strategy to prepare a class of tetracyclic cyclopenta-fused spiroindoline skeletons by joining the indole and cyclopropane with a linker (Scheme 1). Here, we describe the development of
Lewis acid
L
solvent
yield (%)b
dr (2/3)c,d
1 2 3 4 5 6 7e 8e 9e 10e 11e
Sc(OTf)3 Cu(SbF6)2 Cu(SbF6)2 Cu(SbF6)2 Cu(SbF6)2 Cu(SbF6)2 Cu(SbF6)2 Cu(SbF6)2 Cu(SbF6)2 Cu(SbF6)2 Cu(SbF6)2
− L1 L2 L3 L4 L5 L3 L3 L3 L3 L3
DCE DCE DCE DCE DCE DCE DCE toluene THF CH3CN DMSO
80 57 55 61 87 26 83 73 trace NR NR
50/50 66/34 75/25 83/17 55/45 54/46 83/17 81/19 76/24 − −
a
Conducted on 0.25 mmol scale, solvent (4 mL), reaction time: 4−48 h. bIsolated yields of products 2 and 3. cDetermined by 1H NMR spectroscopy of the crude products. dThe cis isomer is defined by Hatoms on the tertiary carbon which are on the same side of the cyclopentyl ring. The trans is defined by H-atoms on the tertiary carbon which are on opposite sides of the cyclopentyl ring. eAt 30 °C.
Scheme 1. Newly-Designed Intramolecular [3+2] Annulation Approach to Tetracyclic Spiroindolines
Unfortunately, the diastereoselectivity is very poor. Then we explored the common strategies8 such as by optimizing the Lewis acids,8a reaction conditions,8b−f and ligands8g to improve the stereoselectivity. When In(OTf)3 and Cu(ClO4)2·6H2O were employed, poor diastereoselectivities were obtained (see Supporting Information (SI), Table S1, entries 2 and 11). By using Zn(OTf)2, the annulation was sluggish (Table S1, entry 8).
this approach to tetracyclic spiroindolines with three continuous stereocenters including an all-carbon quaternary stereocenters in a five-membered ring. In particular, we observed that the diastereoselectivity of this new reaction can be switched by changing the remote ester groups of cyclopropanes: the isopropyl ester is highly favorable for the trans diastereomer, while the 2-adamantyl ester is the best for the cis one. The origins © 2014 American Chemical Society
entrya
Received: March 27, 2014 Published: April 25, 2014 6900
dx.doi.org/10.1021/ja503117q | J. Am. Chem. Soc. 2014, 136, 6900−6903
Journal of the American Chemical Society
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To investigate the generality of this reaction, we synthesized a variety of cyclopropanes 1 with 2-propyl and 2-adamantyl ester groups. Under the optimal conditions, we first evaluated with isopropyl esters (iPr-1) for the synthesis of trans product 2. As shown in Table 3, substituents such as F, Cl, Br, and alkyl on the
When the reaction was catalyzed by Cu(SbF6)2 (10 mol %) in the presence of diimine ligand L1, we were pleased to find that the reaction speeded up significantly and finished in 4 h with 66/34 dr in 57% yield (entry 2). More hindered diimine ligands provide better stereoselectivities (entries 2−4). To our delight, when N2,6-diisopropylphenyl diimine L3 was employed as the ligand, the yield and diastereoselectivity increased to 61% and 83/17, respectively (entry 4). Other ligands such as bisoxazoline L4 and bipyridine L5 were also examined, but resulted in poor diastereoselectivities (55/45 and 54/46 dr, entries 5 and 6). Lowering the reaction temperature to 30 °C afforded an 83% yield without erosion of diastereoselectivity (entry 7). Solvent screening showed that toluene could lead to a 73% yield and 81/ 19 dr, but THF, acetonitrile, and DMSO proved to be unsuitable in this reaction (entries 8−11). After hundreds of trials failed to improve the diastereoselectivity to a satisfactory result (for details, see SI), we focused on changing the ester R group of the cyclopropane. As shown in Table 2, when the R group of the ester was changed from ethyl to
Table 3. Reaction Scope with Isopropyl Esters
Table 2. Effect of Ester Groups
entrya
R′
R
yield (%)b
dr (2/3)c
1 2 3 4 5 6 7 8 9 10 11 12 13
H H H H H H H H H H H CH3 CH3
Et Me nHex iPr cHex 3-Pent tBu 1-Ad CH2tBu CH2-1-Ad 2-Ad iPr 2-Ad
83 87 77 77 83 45 trace trace 64 52 61 85 79
83/17 74/26 78/22 90/10 88/12 89/11 − − 15/85 9/91 6/94 84/16 5/95
entrya
R
product
yield (%)b
dr (trans/cis)c
1 2 3 4 5 6 7 8 9 10 11 12 13
H 5-Me 5-F 5-Cl 5-Br 6-F 6-Cl 7-Me 7-Br 4-Me 4-F 4-Cl 4-Br
2ad 2b 2c 2d 2e 2f 2g 2h 2i 2j 2k 2l 2m
77 71 77 84 83 60 73 80 84 50 71 68 81
90/10 94/6 93/7 93/7 93/7 88/12 89/11 91/9 94/6 >99/1 95/5 >99/1 >99/1
a
Conducted on 0.25 mmol scale, DCE (4 mL). bIsolated yields. Determined by 1H NMR spectroscopy of the crude products. d Confirmed by X-ray diffraction analysis. c
indole, as well as different substitution patterns (4, 5, 6, 7-), are well tolerated in the reaction, giving the desired products in good yields with high diastereoselectivities (from 88/12 to >99/1 dr, entries 2−11). With electron-donating and -withdrawing groups at different positions of the aromatic ring of indole, in cases of 2adamantyl ester substrates (Ad-1), the reactions showed good reactivity and excellent diastereoselectivities affording cis tetracyclic spiroindolines 3 (72−95% yield, 93/7−96/4 dr; Table 4, entries 2−10). In addition, the reactions in Tables 3 and Table 4. Reaction Scope with 2-Adamantyl Esters
a
Conducted on 0.25 mmol scale, DCE (4 mL). bIsolated yields of products 2 and 3. cDetermined by 1H NMR spectroscopy of the crude products. Pent = pentyl; Ad = adamantyl.
methyl, the diastereomeric ratio was decreased to 74/26 (entry 2), suggesting that the ester groups on the cyclopropane ring may have a significant influence on the selectivity. Therefore, a variety of substrates 1 with different ester groups were examined in this intramolecular [3 + 2] annulation. It was found that changing the ester R group from a primary to secondary alkyl group can improve the diastereoselectivity greatly (entries 2−6).9 The isopropyl group proved to be optimal with respect to the selective synthesis of trans diastereomer 2 (2/3: 90/10, entry 4). Continuing to increase the size of esters by introducing tertiary alkyl groups, such as tert-butyl and 1-adamantyl, destroyed the reactivity (entries 7−8). To our surprise, a sudden inversion of selectivity to cis diastereomer 3 (2/3: 15/85, entry 9) was observed when neo-pentyl ester was used, and the cis/trans ratio can be further elevated to 94/6 by employing the 2-adamantyl group (entry 11). This diastereo-divergence switched by the ester group was also observed in the reactions using the corresponding N-methylindole substrates (entries 12−13).
entrya
R
product
yield (%)b
dr (cis/trans)c
1 2e 3 4 5 6 7 8 9 10e
H 5-OMe 5-Me 5-F 5-Cl 5-Br 6-F 6-Cl 7-Me 4-OMe
3ad 3b 3c 3d 3e 3f 3g 3h 3i 3j
79 95 90 92 93 84 93 91 92 72
95/5 95/5 96/4 95/5 94/6 95/5 93/7 94/6 96/4 95/5
a
Conducted on 0.25 mmol scale, DCE (4 mL). bIsolated yields. Determined by 1H NMR spectroscopy of the crude products. d Confirmed by X-ray diffraction analysis. eWith 20 mol % catalyst. Ad = 2-adamantyl. c
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4 were carried out under very mild conditions and finished within 24 h. The stereochemistries of 2a and 3a were identified by X-ray analysis.10 The current method is suitable to prepare chiral tetracyclic spiroindolines. As shown in Scheme 2, when the optically pure Scheme 2. Synthesis of Chiral Tetracyclic Spiroindolines from Optically Pure Substrates
isopropyl or 2-adamantyl substrate was employed, the chirality from the cyclopropane is completely transferred to the product, similar to the cycloaddition11 of aldehydes and D−A cyclopropanes. The aforementioned results showed excellent generality of the current reaction and that 2-propyl esters iPr-1 gave trans-isomers 2 while 2-adamantyl esters Ad-1 afforded cis-isomers 3. As the 2propyl and 2-adamantyl groups are remote to the first reactive site and both are secondary alkyl groups, it is hard to explain the effect of the ester group on the stereochemistry by only its steric hindrance and electronic properties. To further understand the mechanism of the intramolecular annulation of indole with a D− A cyclopropane, especially the origins of the unique diastereoselectivity control by the remote ester groups, DFT calculations were performed on four reactions with different R groups shown in Scheme 3.12 Once cyclopropane-1,1-dicarbox-
Figure 1. DFT-optimized structures of transition states TS1-trans-R and TS1-cis-R and DFT-computed relative activation Gibbs free energies (R = Me, iPr, CH2tBu, 2-Ad; carbon, gray; nitrogen, blue; oxygen, red; sulfur, yellow; copper, brown; H-atoms are not shown for clarity; distances are given in angstroms).
trans configuration via TS2-trans-R or the cis one via TS2-cis-R (Scheme 3). As shown in Figure 1, for the reaction with the methyl ester, DFT calculations using the ωB97XD13 and B3LYP14 methods indicate that formation of the trans product via TS1-trans-Me is slightly favored, in agreement with the experimental result (Table 2, entry 2). In the case of the isopropyl ester, a better trans selectivity is obtained experimentally (Table 2, entry 4). This trend is only reproduced by the ωB97XD method, which yields better results when describing medium- to long-range electron correlation and dispersion effects than those from the traditional B3LYP method.13,15 As the size of the R group from methyl to isopropyl increases, there is no significant steric repulsion generated between the ester and arene in the transition state TS1-trans-iPr, but the attractive interactions,16 which include dispersion forces,17become stronger. In the Wilcox molecular torsion balance experiment, it was reported that the noncovalent interactions between isopropyl and arene are ∼0.5 kcal mol−1 larger than the methyl-arene interactions in the organic solvent.18 This value is very close to the ωB97XD energy difference for the enhanced trans selectivity (Me: −0.4 kcal mol−1, iPr: −0.7 kcal mol−1, Figure 1). When the R group becomes much bulkier (R = CH2tBu, 2-Ad), the steric repulsions increase dramatically in the transition state TS1-trans-R as evidenced by the elongated forming C−C bond (2.76 vs 2.60−2.62 Å, to avoid steric clashes, Figure 1). Therefore, the formation of cis products via TS1-cisCH2tBu(2-Ad) is preferred.
Scheme 3. DFT Study on Intramolecular [3 + 2] Reactions Involving Different Ester Groups
ylate is activated by a Cu(II) catalyst, the intramolecular indole C3-nucleophilic attack to the cyclopropane C2 carbon generates two diastereomeric intermediates through transition states TS1trans-R and TS1-cis-R, respectively (Figure 1). Computational results show that regardless of the size of the R group, this step is irreversible (for details, see the SI), determining the stereochemistry of final products. The subsequent ring-closure process leads to the cycloadduct with two methine hydrogen atoms in a 6902
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(5) For selected leading references of intermolecular asymmetric anulation of D−A cyclopropane, see: (a) Sibi, M. P.; Ma, Z. H.; Jasperse, C. P. J. Am. Chem. Soc. 2005, 127, 5764. (b) Kang, Y. B.; Sun, X. L.; Tang, Y. Angew. Chem., Int. Ed. 2007, 46, 3918. (c) Parsons, A. T.; Johnson, J. S. J. Am. Chem. Soc. 2009, 131, 3122. (d) Parsons, A. T.; Smith, A. G.; Neel, A. J.; Johnson, J. S. J. Am. Chem. Soc. 2010, 132, 9688. (e) Trost, B. M.; Morris, P. J. Angew. Chem., Int. Ed. 2011, 50, 6167. (f) Xiong, H.; Xu, H.; Liao, S.; Xie, Z.; Tang, Y. J. Am. Chem. Soc. 2013, 135, 7851. (g) Xu, H.; Qu, J. P.; Liao, S.; Xiong, H.; Tang, Y. Angew. Chem., Int. Ed. 2013, 52, 4004. (h) Zhou, Y. Y.; Li, J.; Ling, L.; Liao, S. H.; Sun, X. L.; Li, Y. X.; Wang, L. J.; Tang, Y. Angew. Chem., Int. Ed. 2013, 52, 1452. (6) For selected leading references of intramolecular anulation of cyclopropane, see: (a) Danishefsky, S. Acc. Chem. Res. 1979, 12, 66. (b) Jackson, S. K.; Karadeolian, A.; Driega, A. B.; Kerr, M. A. J. Am. Chem. Soc. 2008, 130, 4196. (c) Xing, S.; Pan, W.; Liu, C.; Ren, J.; Wang, Z. Angew. Chem., Int. Ed. 2010, 49, 3215. (d) Xing, S.; Li, Y.; Li, Z.; Liu, C.; Ren, J.; Wang, Z. Angew. Chem., Int. Ed. 2011, 50, 12605. (e) Bai, Y.; Tao, W.; Ren, J.; Wang, Z. Angew. Chem., Int. Ed. 2012, 51, 4112. (f) Zhu, W.; Fang, J.; Liu, Y.; Ren, J.; Wang, Z. Angew. Chem., Int. Ed. 2013, 52, 2032. (g) Cavitt, M. A.; Phun, L. H.; France, S. Chem. Soc. Rev. 2014, 43, 804. (7) (a) Harrington, P.; Kerr, M. A. Tetrahedron Lett. 1997, 38, 5949. (b) Kerr, M. A.; Keddy, R. G. Tetrahedron Lett. 1999, 40, 5671. (c) England, D. B.; Kuss, T. D.; Keddy, R. G.; Kerr, M. A. J. Org. Chem. 2001, 66, 4704. (d) Bajtos, B.; Yu, M.; Zhao, H.; Pagenkopf, B. L. J. Am. Chem. Soc. 2007, 129, 9631. (e) Larquetoux, L.; Ouhamou, N.; Chiaroni, A.; Six, Y. Eur. J. Org. Chem. 2005, 2005, 4654. (8) For selected leading references, see: (a) Lu, G.; Yoshino, T.; Morimoto, H.; Matsunaga, S.; Shibasaki, M. Angew. Chem., Int. Ed. 2011, 50, 4382. (b) Moteki, S. A.; Han, J.; Arimitsu, S.; Akakura, M.; Nakayama, K.; Maruoka, K. Angew. Chem., Int. Ed. 2012, 51, 1187. (c) Krautwald, S.; Sarlah, D.; Schafroth, M. A.; Carreira, E. M. Science 2013, 340, 1065. (d) Oliveira, M. T.; Luparia, M.; Audisio, D.; Maulide, N. Angew. Chem., Int. Ed. 2013, 52, 13149. (e) Sun, X.-L.; Tang, Y. Acc. Chem. Res. 2008, 41, 937. (f) Deng, X.-M.; Cai, P.; Ye, S.; Sun, X.-L.; Liao, W.-W.; Li, K.; Tang, Y.; Wu, Y.-D.; Da, L.-X. J. Am. Chem. Soc. 2006, 128, 9730. (g) Ding, S.; Song, L.-J.; Chung, L. W.; Zhang, X.; Sun, J.; Wu, Y.-D. J. Am. Chem. Soc. 2013, 135, 13835. (9) When the benzyl ester was examined, a 75% yield with 55/45 (trans/cis) was obtained. (10) CCDC 981305 (2a) and 981312 (3a) contain the supplementary crystallographic data for this paper. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www. ccdc.cam.ac.uk/data_request/cif. (11) Pohlhaus, P. D.; Johnson, J. S. J. Am. Chem. Soc. 2005, 127, 16014. (12) (a) Frisch, M. J. et al. Gaussian 09, Revision C.01; Gaussian, Inc.: Wallingford, CT, 2010. Complete reference is in the SI. (b) Geometry optimizations and frequency calculations were performed at the B3LYP/6-31G(d)-LANL2DZ (for Cu) level. Single-point energy calculations in 1,2-dichloroethane (DCE) using the CPCM model were performed at the B3LYP/6-311G(d,p)-LANL2DZ or ωB97XD/6311G(d,p)-LANL2DZ level. For details, see the SI. (13) Chai, J. D.; Head-Gordon, M. Phys. Chem. Chem. Phys. 2008, 10, 6615. (14) (a) Lee, C.; Yang, W.; Parr, R. G. Phys. Rev. B 1988, 37, 785. (b) Becke, A. D. J. Chem. Phys. 1993, 98, 5648. (15) Fokin, A. A.; Chernish, L. V.; Gunchenko, P. A.; Tikhonchuk, E. Y.; Hausmann, H.; Serafin, M.; Dahl, J. E.; Carlson, R. M.; Schreiner, P. R. J. Am. Chem. Soc. 2012, 134, 13641. (16) Krenske, E. H.; Houk, K. N. Acc. Chem. Res. 2013, 46, 979. (17) Schreiner, P. R.; Chernish, L. V.; Gunchenko, P. A.; Tikhonchuk, E. Y.; Hausmann, H.; Serafin, M.; Schlecht, S.; Dahl, J. E.; Carlson, R. M.; Fokin, A. A. Nature 2011, 477, 308. (18) Bhayana, B.; Wilcox, C. S. Angew. Chem., Int. Ed. 2007, 46, 6833.
In summary, we have succeeded in developing a simple, efficient method for the highly diastereoselective construction of tetracyclic spiroindoline skeletons through Cu(II)-catalyzed intramolecular [3 + 2] reactions of cyclopropane-1,1-dicarboxylates with indoles. Unprecedentedly, the diastereoselectivities of the present reaction could be readily switched by altering the remote ester groups of cyclopropanes: the isopropyl ester is highly favorable for the trans diastereomer, while the 2adamantyl ester is the best for the cis one. Thus, it provides not only a new approach for the remote control of diastereoselection but also a one-step and facile access to both cis- and trans-diastereomers of tetracyclic spiroindolines under the same reaction conditions. DFT calculations show that attractive interactions between the isopropyl ester and arene enhance the trans selectivity, and that the steric repulsions caused by the bulky 2-adamantyl group make the cis product predominant.
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ASSOCIATED CONTENT
S Supporting Information *
Experimental procedures, characterizations and analytical data of products, spectra of NMR and HPLC, and computational details. This material is available free of charge via the Internet at http:// pubs.acs.org.
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AUTHOR INFORMATION
Corresponding Authors
[email protected] [email protected] Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS We are grateful for the financial support from the National Natural Sciences Foundation of China (Nos. 21121062, 20932008, and 21272250), the Chinese Academy of Sciences, and the U.S. National Science Foundation (CHE-1059084). We thank Dr. Xue-bing Leng (SIOC) and Mr. Jie Sun (SIOC) for Xray crystal analysis.
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REFERENCES
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